It is well known that IgE antibodies against allergens (antigens) cause allergic diseases such as pollinosis. The role of IgE antibodies in the allergic diseases raised the possibility that the regulation and suppression of the IgE antibody formation against allergens would be one of the fundamental treatments of allergic diseases. In recent years, desensitization treatment in which allergic patients receive repeated injections of a minute dose of allergen is performed in actual clinical fields. Although the desensitization treatment can improve clinical symptoms in some patients, it involves the risk of causing anaphylactic shock. Hence, the desensitization treatment is performed only for limited patients under sufficient monitoring.
For the purpose of solving the aforementioned problem, an attempt was made to inject a modified antigen which does not bind to antibodies against native antigens. However, the IgE antibody titer of patients did not decline after the treatment. In the meantime, it was found that the injection of a modified antigen induced not only helper T cells but also antigen-specific suppressor T cells and that the transfer of the antigen-specific suppressor T cells suppressed ongoing IgE formation induced by immunization (Takatsu and Ishizaka, J. Immunol., 117,:211, 1976). These findings suggest that it is possible to suppress ongoing IgE formation if antigen-specific suppressor T cells, not helper T cells, can selectively be induced without expanding the population of helper T cells.
In the 1980's, two types of T-cell factors that would bind to IgE for selectively regulating the IgE formation were found in the course of studies on the regulation of IgE formation. One of the IgE-binding factors enhances the IgE formation, while the other type of IgE-binding factor suppresses the IgE formation. The structures of the IgE-potentiating factors and IgE-suppressive factors are similar in protein moieties but different in carbohydrate moieties. The IgE-potentiating factor has a high-mannose N-linked carbohydrate and binds to lentil lectin. The IgE-suppressive factor does not have affinity for lentil lectin (Yodoi, et al, J. Immunol., 128:289, 1982). It was shown that the IgE-potentiating factor and IgE-suppressive factor have different biological properties depending on the difference in the structure of the carbohydrate moieties. Under physiological conditions, the glycosylation process of the IgE-binding factors is controlled by two T-cell factors which either enhance or inhibit this process. A factor which enhances the glycosylation to produce the IgE-potentiating factor is denominated glycosylation enhancing factor (GEF) and a factor which inhibits the glycosylation to produce the IgE-suppressive factor is denominated glycosylation inhibiting factor (GIF). In experimental animals, GEF is always produced when the IgE formation is enhanced and GIF is always produced when the IgE formation is suppressed. Hence, it was believed that the balance of GEF and GIF would determine the properties of the IgE binding factors, thus controlling the IgE formation.
A subsequent study revealed that GIF-producing T cells were antigen-specific suppressor T cells (Jardieu et al., J. Immunol., 133:3266, 1984). In a study using ovalbumin (OVA)-specific suppressor T cell hybridomas, it was found that the cells produced GIF constitutively and that the GIF did not exhibit specificity to antigens (antigen non-specific GIF). It was additionally found that the production of GIF having affinity for ovalbumin (antigen-specific GIF) was induced by stimulating the cells with ovalbumin and antigen-presenting cells. The antigen-specific GIF was composed of an antigen-binding polypeptide chain and a non-specific GIF (Jardieu and Ishizaka, Immune Regulation by Characterized Polypeptides, edited by Goldstein et al., Alan R. Liss, Inc., New York, page 595, 1987). It was revealed that the antigen-specific GIF shared common antigenic determinants with antigen-specific suppressor T-cell factors (Steele, J. K. et al., J. Immunol., 142: 2213, 1989) and that the antigen-specific GIF suppressed the antibody response in an antigen (carrier)-specific manner (Jardieu, P. et al, J. Immunol., 138:1494, 1987). It was also found that the production of ovalbumin-specific GIF was induced by injecting non-specific GIF into ovalbumin-primed mice and then stimulating their spleen cells with ovalbumin (Akasaki, M. et al, J. Immunol., 136:3172, 1986).
Recently, the inventors have succeeded in isolating GIF from murine suppressor T cells and cloning a murine antigen non-specific GIF gene. Furthermore, they have obtained a human gene by using the GIF gene as a probe (Mikayama, T. et al., Proc. Natl. Acad Sci. USA, 90:10056, 1993). When the gene was expressed directly in E. coli or an animal cell as a host by a gene recombinant technique, the produced recombinant GIF exhibited extremely low biological activity compared to the GIF derived from suppressor T cells. Only when the gene was expressed in an animal host cell in the form of a fusion protein which is translocated into endo-plasmic reticulum, the produced recombinant GIF exhibited a biological activity comparable to the GIF derived from suppressor T cells. Thereafter, it was shown that some post-translational modification of GIF peptide was required for generation of a sufficiently high biological activity (Liu, Y-C. et al., Proc. Natl. Acad Sci. USA, 91:11227, 1994). As the structural studies of GIF are difficult to be accomplished with a limited amount of purified protein, structures essential for biologic activities are unknown at present.
It is expected that injections of antigen-specific GIF per se or non-specific GIF capable of inducing antigen-specific suppressor T cells is very effective in the treatments of allergy. Such treatment requires production of a large quantity of GIF having a sufficiently high biological activity by a recombinant DNA technique. However, since the molecular mechanisms for the generation of highly bioactive GIF is unknown, no one has ever succeeded in producing recombinant GIF derivative having a sufficiently high biological activity.